KEYNOTE-905: EV/pembrolizumab emerges as new option for cisplatin-ineligible MIBC

A treatment regimen consisting of neoadjuvant enfortumab vedotin-ejfv (EV, Padcev) plus pembrolizumab (Keytruda), radical cystectomy (RC) plus pelvic lymph node dissection (PLND), and adjuvant EV plus pembrolizumab yielded significant improvements in multiple outcomes in patients with muscle-invasive bladder cancer who are ineligible for or decline cisplatin-based chemotherapy.^1,2

The data, from the phase 3 KEYNOTE-905 trial (NCT03924895), were presented to rounds of applause during a session at the 2025 European Society for Medical Oncology Congress in Berlin, Germany.

Principal investigator Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent (IKG, Belgium) and Clinical Trial Unit Oncology Ghent, began his presentation by explaining that although neoadjuvant cisplatin-based chemotherapy and RC plus PLND represents the current standard of care in MIBC,^3,4 almost 50% of patients with MIBC are ineligible for cisplatin.^5-8

For KEYNOTE-905, investigators sought to evaluate perioperative EV plus pembrolizumab with RC plus PLND vs RC plus PLND alone in patients with MIBC who are ineligible for or decline cisplatin-based chemotherapy.

Adults with MIBC of clinical stage T2-T4aN0M0 or T1-T4aN1M0 by central assessment, 50% or greater urothelial histology, cisplatin ineligibility per Galsky criteria or declined cisplatin, and ECOG performance status of 0-2 were eligible for inclusion. Patients were stratified according to cisplatin ineligibility (ineligible vs eligible but declining), clinical stage (T2N0 vs T3/T4aN0 vs T1-4aN1), and region (US vs European Union vs most of world).

The study included 3 arms: an experimental arm consisting of perioperative pembrolizumab 200 mg intravenously (IV) every 3 weeks for 3 cycles followed by RC plus PLND followed by pembrolizumab 200 mg IV every 3 weeks for 14 cycles; an experimental arm consisting of perioperative EV 1.25 mg/kg day 1 and day 8 IV every 3 weeks for 3 cycles plus pembrolizumab 200 mg IV every 3 weeks for 3 cycles followed by RC plus PLND followed by EV 1.25 mg/kg day 1 and day 8 IV every 3 weeks for 6 cycles plus pembrolizumab 200 mg IV every 3 weeks for 14 cycles; and a control arm consisting of RC plus PLND only. The primary end point was event-free survival (EFS) as assessed by blinded independent central review. Key secondary end points included overall survival (OS) and pathological complete response (pCR). Another secondary end point was safety. EFS by pCR status was an exploratory end point. In 2022, random assignment to the pembrolizumab arm was stopped.

A total of 170 patients were randomly assigned to the EV plus pembrolizumab arm and 174 patients were randomly assigned to the control arm.

“The vast majority of these patients randomized to the EV/P arm completed their neoadjuvant treatment. The proportion of patients not undergoing surgery was similar between both arms, most commonly because of patient withdrawal,” Vulsteke commented.

Discussing baseline patient characteristics, Vulsteke made several observations. The median patient age in the EV plus pembrolizmab arm was 74.0 years (range, 47-87 years), “which is older than in other MIBC trials,” Vulsteke said.

In addition, 21 (12.4%) patients in the EV plus pembrolizumab arm had an ECOG performance status of 2.

“These patients are typically excluded from other MIBC trials,” Vulsteke observed.

The study met its primary end point. The median EFS was not reached (NR) in the EV plus pembrolizumab arm (95% CI: 37.3-NR) vs 15.7 months in the control arm (95% CI: 10.3-20.5) (HR, 0.40, 95% CI: 0.28-0.57, one-sided P < .0001). The EFS benefits were observed across subgroups in the study.

Median OS was NR in the EV plus pembrolizumab group (95% CI: NR-NR) vs 41.7 months in the control group (95% CI: 31.8-NR) (HR, 0.50, 95% CI: 0.33-0.74, one-sided P = .0002).

“This is the first trial to show an overall survival benefit in this population,” Vulsteke noted. Like EFS, the OS gains were observed across patient subgroups.

Ninety-seven patients in the EV plus pembrolizumab group achieved a pCR vs 15 patients in the control group. The pCR rate was 57.1% (95% CI: 49.3-64.6) in the EV plus pembrolizumab group vs 8.6% (95% CI: 4.9-13.8) in the control group.

For patients receiving EV plus pembrolizumab who had a pCR, median EFS was NR (95% CI: NR-NR) vs 41.2 months (95% CI: 12.7-NR) (HR, 0.43, 95% CI: 0.16-0.16) in the control arm. For patients receiving EV plus pembrolizumab who did not have a pCR, median EFS was 26.1 months (95% CI: 10.1-41.2) vs 14.2 months (95% CI: 10.1-19.5) in the control arm.

Any-grade treatment-emergent adverse events (TEAEs) were reported in 167 (100%) patients in the EV plus pembrolizumab group vs 103 (64.8%) patients in the control group. Grade 3 or higher TEAEs were seen in 119 (71.3%) patients in the EV plus pembrolizumab group vs 73 (45.9%) patients in the control group. TEAEs leading to dose reduction of EV occurred in 28 (16.8%) patients, TEAEs leading to discontinuation of EV occurred in 69 (41.3%) patients, TEAEs leading to discontinuation of pembrolizumab occurred in 57 (34.1%) patients, and TEAEs leading to death occurred in 13 (7.8%) patients in the EV plus pembrolizumab arm vs 9 (5.7%) patients in the control arm.

“In summary, neoadjuvant enfortumab vedotin plus pembrolizumab, followed by surgery and adjuvant enfortumab vedotin and pembrolizumab significantly and meaningfully improved all end points of event-free survival, overall survival, and pCR in participants with MIBC who are ineligible for or declined cisplatin-based chemotherapy, and this benefit was generally consistent across key subgroups. Peri-op EV/P did not impact the ability of these participants to undergo curative intent surgery. The safety profile of peri-op EV/P was manageable and consistent with prior reports of this regimen in the metastatic setting. KEYNOTE-905 is the first phase 3 trial to show an improved efficacy outcome with peri-op therapy relative to surgery for patients with MIBC who are ineligible for cisplatin-based chemotherapy. Perioperative enfortumab vedotin and pembrolizumab added to surgery may represent a new standard of care in this population with a high unmet medical need,” Vulsteke said in conclusion.

DISCLOSURES: Vulsteke noted research funding and medical writing support from Merck Sharp & Dohme LLC (MSD); advisory board participation with MSD, Janssens-Cilag, GSK, Astellas Pharma, BMS, Leo Pharma, Bayer, AstraZeneca, Pfizer, Merck, and Athenum Partners; and institutional research funding from MSD.

REFERENCES

1. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The phase III KEYNOTE-905 study. Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA2. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA2.html.pdf

2. PADCEV plus KEYTRUDA, given before and after surgery, cuts the risk of recurrence, progression or death by 60% and the risk of death by 50% for certain patients with bladder cancer. News release. Astellas Pharma. https://www.prnewswire.com/news-releases/padcev-plus-keytruda-given-before-and-after-surgery-cuts-the-risk-of-recurrence-progression-or-death-by-60-and-the-risk-of-death-by-50-for-certain-patients-with-bladder-cancer-302587853.html

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4. National Comprehensive Cancer Network Guidelines: Bladder Cancer. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1417

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